In this Cutting-Edge Basic Research Award (CEBRA) proposal, an electrical engineer/computer scientist (PI Mohseni) and a neurobiologist/analytical chemist (PI Garris) will collaborate to develop an ultra-small, implantable device for wireless neural monitoring and stimulation in awake animals. This device will advance the investigation of biologic mechanisms of drug addiction by extending recent innovations in fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM). By virtue of chemically selective recording with sub-second temporal resolution at a micron-sized probe, FSCV at a CFM is recognized as state-of-the-art for neurotransmitter monitoring. In the last decade, great strides have been made applying FSCV at a CFM to ambulatory rats for studying the role of phasic dopaminergic transmission in goal-directed behaviors, particularly with regard to cocaine reinforcement, and combining chemical and electrical measurements at the same probe for quantifying postsynaptic effects of brain dopamine dynamics. By extending the already attractive analytical attributes of FSCV at a CFM on several fronts, we firmly believe that the device proposed here meets criteria for the CEBRA program. Proposed developments include: (1) replacing the hardwired connection with a digital telemetry link;(2) replacing the external stimulus generator with an on-chip component;(3) significantly reducing overall dimensions, weight, and power consumption;(4) supporting multiple, independently configurable channels for FSCV, electrophysiology, and combined measurements. Collectively, these advances address concerns related to the current use of "large" head-mounted devices as well as tethering animals to equipment, which may alter behavior, act as a noise source, and preclude measurements in smaller, but valuable animal models such as transgenic mice. Moreover, multiple data channels afford the enticing prospect of marrying two powerful technologies for neural monitoring, FSCV at a CFM and multielectrode array single-unit recording, to assess complex circuit-level control of drug-related behavior on an integrative level. The three specific aims are to: (1) using very-large-scale-integration techniques in standard complementary-metal-oxide-semiconductor technology, develop a 16-channel device supporting voltammetry, electrophysiology, and combined measurements, as well as electrical stimulation;(2) test and characterize the device on several levels, including benchtop engineering assessment, in vitro calibration with flow injection analysis, and anesthetized and awake rats;(3) showcase device features in two pilot applications, FSCV dopamine measurements in the awake rat during high-dose administration of the psychostimulant amphetamine and single-unit recording with microwire bundles chronically implanted in a transgenic mouse model. By developing the first wireless integrated circuit supporting chemical and electrical sensing and electrical stimulation, this CEBRA proposal will address key limitations of existing instrumentation for FSCV at a CFM and advance this already powerful neural monitoring technique. PUBLIC HEALTH RELEVANCE: This project will develop a miniaturized wireless device supporting chemical and electrical recording as well as electrical stimulation in the brain of small laboratory animals. This device will advance basic science research investigating neural mechanisms of drug addiction.